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PLoS Biol. 2018 Aug 24;16(8):e2002979. doi: 10.1371/journal.pbio.2002979. eCollection 2018 Aug.

A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy.

Author information

1
Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
2
The National Institute for Biotechnology in the Negev (NIBN), Beer-Sheva, Israel.
3
Department of Physiology and Cell Biology, Regenerative Medicine and Stem Cell Research Center (RMSC), Ben-Gurion University of the Negev, Beer-Sheva, Israel.
4
Faculty of Engineering, Holon Institute of Technology, Holon, Israel.

Abstract

There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and αvβ3 integrin, which act in concert to facilitate bone resorption by osteoclasts. Using functional fluorescence-activated cell sorting (FACS)-based screening assays of random mutagenesis macrophage colony-stimulating factor (M-CSF) libraries against c-FMS and αvβ3 integrin, we engineered dual-specific M-CSF mutants with high affinity to both receptors. These bispecific mutants act as functional antagonists of c-FMS and αvβ3 integrin activation and hence of osteoclast differentiation in vitro and osteoclast activity in vivo. This study thus introduces a versatile platform for the creation of new-generation therapeutics with high efficacy and specificity for osteoporosis and other bone diseases. It also provides new tools for studying molecular mechanisms and the cell signaling pathways that mediate osteoclast differentiation and function.

PMID:
30142160
PMCID:
PMC6126843
DOI:
10.1371/journal.pbio.2002979
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors have declared that no competing interests exist.

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